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  • C07D—HETEROCYCLIC COMPOUNDS
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  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• This invention relates to morpholine derivatives and their use as pharmaceuticals.
• Polypeptides and polynucleotides encoding the human 7-transmembrane G-protein coupled neuropeptide receptor, orexin-1 have been identified and are disclosed in EP-A-875565, EP-A-875566 and WO 96/34877.
• Polypeptides and polynucleotides encoding a second human orexin receptor, orexin-2 have been identified and are disclosed in EP-A-893498.
• polypeptides and polynucleotides encoding polypeptides which are ligands for the orexin-1 receptor, e.g. orexin-A (Lig72A) are disclosed in EP-A-849361.
• Orexin receptors are found in the mammalian host and may be responsible for many biological functions, including pathologies including, but not limited to, depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis/disorder; depressive neurosis/disorder; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delerium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Gilles de la Tourett's syndrome; disturbed biological and circadian rhythms; feeding disorders, such as anorexia, bulimia, cachexia, and obesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic
• HIV, post-polio syndrome, and post-herpetic neuralgia phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain including irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g.
• narcotics or withdrawal from narcotics sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; and neurodegenerative disorders, which includes nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.
• Rat sleep/EEG studies have also shown that central administration of orexin-A, an agonist of the orexin receptors, causes a dose-related increase in arousal, largely at the expense of a reduction in paradoxical sleep and slow wave sleep 2, when administered at the onset of the normal sleep period. Therefore antagonists of its receptor may be useful in the treatment of sleep disorders including insomnia.
• the present invention provides morpholine derivatives which are non-peptide antagonists of human orexin receptors, in particular orexin-1 receptors.
• these compounds are of potential use in the treatment of obesity, including obesity observed in Type 2 (non-insulin-dependent) diabetes patients, and/or sleep disorders, and/or stroke, particularly ischemic or haemorrhagic stroke.
• R 1 is phenyl, naphthyl, a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; any of which may be optionally substituted;
• R 2 represents phenyl or a 5- or 6-membered heteroaryl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heteroaryl group is substituted by R 3 , and further optional substituents; or R 2 represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S;
• R 3 represents an optionally substituted (C 1-4 )alkoxy, halo, optionally substituted (C 1-6 )alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclic ring containing up to 3 heteroatoms selected from N, O and S;
• R 1 is a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S, include pyridyl, furanyl, indolyl, benzofuranyl, quinolinyl, isoquinolinyl, pyrazinyl, quinoxalinyl, benzoxazolyl, pyrazolyl and isoxazolyl.
• R 1 is an optionally substituted phenyl, benzofuranyl, quinolinyl, indolyl or benzoxazolyl.
• the group may have up to 5, preferably 1, 2 or 3 optional substituents.
• R 2 represents a 5- or 6-membered heteroaryl group containing up to 3 heteroatoms selected from N, O and S, include thiazolyl, pyrazolyl, triazolyl, pyridazyl and isoxazolyl.
• R 2 represents phenyl, or a 5- or 6-membered heterocyclyl group the substituent R 3 is adjacent to the point of attachment to the amide carbonyl group.
• R 2 represents optionally substituted thiazolyl.
• Particular R 2 groups incorporating the R 3 substituent, that may be mentioned are 4-(2-methyl-5-(4-fluorophenyl))thiazolyl, 4-(2-methyl-5-(3-fluorophenyl))thiazolyl, 4-(2-methyl-5-(2-fluorophenyl))thiazolyl, and 4-(2-methyl-5-phenyl)thiazolyl, specifically 4-(2-methyl-5-(4-fluorophenyl))thiazolyl.
• R 3 may be a trifluoromethoxy group, halo, (C 4-6 )alkyl, optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclyl ring contains up to 3 heteroatoms selected from N, O and S.
• R 3 is a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl.
• R 3 represents trifluoromethoxy, methoxy, halo, or optionally substituted phenyl, pyridyl, pyrazolyl or oxadiazolyl group.
• R 3 represents an optionally substituted phenyl, e.g. 4-fluorophenyl.
• R 3 represents a pyridyl group.
• Optional substituents for the groups R 1 to R 3 include halogen, hydroxy, oxo, cyano, nitro, (C 1-4 )alkyl, (C 1-4 )alkoxy, halo(C 1-4 )alkyl, halo(C 1-4 )alkoxy, aryl(C 1-4 )alkoxy, (C 1-4 )alkylthio, hydroxy(C 1-4 )alkyl, hydroxy(C 1-4 )alkoxy, (C 1-4 )alkoxy(C 1-4 )alkyl, (C 3-6 )cycloalkyl(C 1-4 )alkoxy, (C 1-4 )alkanoyl, (C 1-4 )alkoxycarbonyl, (C 1-4 )alkylsulfonyl, (C 1-4 )alkylsulfonyloxy, (C 1-4 )alkylsulfonyl(C 1-4 )alkyl, aryl
• Preferred substituents are (C 1-4 )alkyl, (C 1-4 )alkoxy, either of which may be optionally substituted, halogen and cyano.
• R 1 may be optionally substituted by a phenyl ring optionally substituted by a halogen, cyano, or C 1-4 alkanoyl or C 1-4 alkylsulfonyl group; or by a 5- or 6-membered heterocyclic ring, optionally substituted by a (C 1-2 )alkyl or R a R b N-group; wherein R a and R b are as defined above.
• substituents positioned ortho to one another may be linked to form a fused ring, e.g. giving a group which is 2,3-ethylenedioxyphenyl.
• halogen atom When a halogen atom is present in the compound of formula (I) it may be fluorine, chlorine, bromine or iodine.
• the alkyl group may be straight chain, branched or cyclic, or combinations thereof, it is preferably methyl or ethyl.
• compounds of formula (I) may exist as R or S enantiomers.
• the present invention includes within its scope all such isomers, including mixtures. Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoismers, including mixtures thereof.
• the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
• Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable derivatives.
• pharmaceutically acceptable derivative includes any pharmaceutically acceptable salt, ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolic or residue thereof.
• salts of the compounds of formula (I) should be pharmaceutically acceptable.
• suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
• Other salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
• Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid.
• the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
• the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
• R 1 and R 2 are as defined for formula (I), P is a protecting group and L 1 and L 2 are leaving groups.
• step (iv) conveniently utilises catalytic hydrogenolysis in an inert solvent (e.g. using palladium on charcoal in a lower alcohol or ethyl acetate).
• an inert solvent e.g. using palladium on charcoal in a lower alcohol or ethyl acetate.
• Suitable leaving groups L 1 and L 2 include halogen, hydroxy, OC( ⁇ O)alkyl OC( ⁇ O)O-alkyl and OSO 2 Me.
• Steps (iii) and (v) may be carried out using a wide range of known acylation conditions, e.g. in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine.
• these steps may be carried out when L 1 or L 2 represents hydroxy, in which case the reaction takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and an activator such as 1-hydroxybenzotriazole.
• a diimide reagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
• an activator such as 1-hydroxybenzotriazole.
• R 1 and R 2 are as defined for formula (I), P and P 1 are amino protecting groups as described for Scheme 1 and L 1 and L 2 are leaving groups as described for Scheme 1.
• protecting groups P and P 1 include t-butyloxycarbonyl, trifluoroacetyl, benzyloxycarbonyl and optionally substituted benzyl.
• Deprotection conditions, step (iv) and (vi), will depend on the particular protecting group; for the groups mentioned above these are respectively, acid (e.g. trifluoroacetic acid in dichloromethane), base (e.g. potassium carbonate in a solvent such as aqueous methanol) and catalytic hydrogenolysis in an inert solvent (e.g. using palladium on charcoal in a lower alcohol or ethyl acetate).
• acid e.g. trifluoroacetic acid in dichloromethane
• base e.g. potassium carbonate in a solvent such as aqueous methanol
• catalytic hydrogenolysis in an inert solvent e.g. using palladium on charcoal in a lower alcohol or ethyl acetate.
• protecting groups P and P 1
• Schemes 1 and 2 illustrate the synthesis of racemic compounds of formula (I), from (RS)-4-benzyl-5-oxomorpholine-3-carboxuylic acid which may be synthesisied from (DL)-serine as described in G. R. Brown, A. J. Foubister and B. Wright, J. Chem Soc. Perkin Trans. I , 1985, 2577. Starting from (D)- or (L)-serine, synthetic methods known to those skilled in the art may be used to give single enantiomers of the compounds of formula (I).
• the compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, e.g. 5 to 1000, preferably 10 to 100 compounds of formula (I).
• Compound libraries may be prepared by a combinatorial ‘split and mix’ approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
• a compound library comprising at least 2 compounds of formula (I), or pharmaceutically acceptable derivatives thereof.
• compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
• the compounds of formula (I) and their pharmaceutically acceptable derivatives are useful for the treatment of diseases or disorders where an antagonist of a human orexin receptor is required such as obesity and diabetes; prolactinoma; hypoprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; Cushings syndrome/disease; hypothalamic-adrenal dysfunction; dwarfism; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases; depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis/disorder; depressive neurosis/disorder; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delerium; dementia; bulimia and hypopituita
• the compounds of formula (I) and their pharmaceutically acceptable derivatives are particularly useful for the treatment of obesity, including obesity associated with Type 2 diabetes, and sleep disorders. Additionally the compounds are useful for the treatment of stroke.
• diseases or disorders which may be treated in accordance with the invention include disturbed biological and circadian rhythms; adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma; adrenohypophysis hypofunction; functional or psychogenic amenorrhea; adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection e.g.
• HIV, post-polio syndrome and post-herpetic neuralgia phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; and tolerance to narcotics or withdrawal from narcotics.
• the invention also provides a method of treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable derivative thereof.
• the invention also provides a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for use in the treatment or prophylaxis of diseases or disorders where an antagonist of a human orexin receptor is required.
• the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders where an antagonist of a human orexin receptor is required.
• the compounds of the invention are usually administered as a pharmaceutical composition.
• the invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
• the compounds of formula (I) and their pharmaceutically acceptable derivatives may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration, and the pharmaceutical compositions adapted accordingly.
• the compounds of formula (I) and their pharmaceutically acceptable derivatives which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.
• a liquid formulation will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
• a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
• the formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
• a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.
• a composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
• suitable pharmaceutical carrier(s) e.g. aqueous gums, celluloses, silicates or oils
• Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parentally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
• a sterile aqueous carrier or parentally acceptable oil e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
• the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
• compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
• Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device.
• the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve.
• the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.
• compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
• a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
• compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
• compositions suitable for transdermal administration include ointments, gels and patches.
• composition is in unit dose form such as a tablet, capsule or ampoule.
• the dose of the compound of formula (I), or a pharmaceutically acceptable derivative thereof, used in the treatment or prophylaxis of the abovementioned disorders or diseases will vary in the usual way with the particular disorder or disease being treated, the weight of the subject and other similar factors.
• suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 500 mg.
• Unit doses may be administered more than once a day for example two or three times a day, so that the total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a number of weeks or months.
• pharmaceutically acceptable derivatives the above figures are calculated as the parent compound of formula (I).
• Human orexin-A has the amino acid sequence as in SEQ ID NO: 1: pyroEPLPDCCRQKTCSCRLYELLHGAGNHAAGILTL-NH 2 .
• Orexin-A can be employed in screening procedures for compounds which inhibit the ligand's activation of the orexin-1 receptor.
• screening procedures involve providing appropriate cells which express the orexin-1 receptor on their surface.
• Such cells include cells from mammals, yeast, Drosophila or E. coli .
• a polynucleotide encoding the orexin-1 receptor is used to transfect cells to express the receptor.
• the expressed receptor is then contacted with a test compound and an orexin-1 receptor ligand to observe inhibition of a functional response.
• One such screening procedure involves the use of melanophores which are transfected to express the orexin-1 receptor, as described in WO 92/01810.
• Another screening procedure involves introducing RNA encoding the orexin-1 receptor into Xenopus oocytes to transiently express the receptor.
• the receptor oocytes are then contacted with a receptor ligand and a test compound, followed by detection of inhibition of a signal in the case of screening for compounds which are thought to inhibit activation of the receptor by the ligand.
• Another method involves screening for compounds which inhibit activation of the receptor by determining inhibition of binding of a labelled orexin-1 receptor ligand to cells which have the receptor on their surface.
• This method involves transfecting a eukaryotic cell with DNA encoding the orexin-1 receptor such that the cell expresses the receptor on its surface and contacting the cell or cell membrane preparation with a compound in the presence of a labelled form of an orexin-1 receptor ligand.
• the ligand may contain a radioactive label. The amount of labelled ligand bound to the receptors is measured, e.g. by measuring radioactivity.
• Yet another screening technique involves the use of FLIPR equipment for high throughput screening of test compounds that inhibit mobilisation of intracellular calcium ions, or other ions, by affecting the interaction of an orexin-1 receptor ligand with the orexin-1 receptor.
• MDC represents methylene dichloride
• THF represents tetrahydrofuran
• DMSO represents methyl sulphoxide
• the orexin-1 receptor antagonist activity of the compounds of formula (I) was determined in accordance with the following experimental method.
• HEK293 cells expressing the human orexin-1 receptor were grown in cell medium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4 mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL.
• the cells were seeded at 20,000 cells/100 ⁇ l/well into 96-well black clear bottom sterile plates from Costar which had been precoated with 10 ⁇ g/well of poly-L-lysine from SIGMA. The seeded plates were incubated overnight at 37° C. in 5% CO 2 .
• Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC 50 values (the concentration required to produce 50% maximal response) were estimated using 11 ⁇ half log unit dilutions (Biomek 2000, Beckman) in Tyrode's buffer containing probenecid (10 mM HEPES with 145 mM NaCl, 10 mM glucose, 2.5 mM KCl, 1.5 mM CaCl 2 , 1.2 mM MgCl 2 and 2.5 mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO (100%).
• Antagonist IC 50 values (the concentration of compound needed to inhibit 50% of the agonist response) were determined against 3.0 nM human orexin-A using 11 ⁇ half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid.
• EC 50 was the potency of human orexin-A determined in the assay (in nM terms) and IC 50 is expressed in molar terms.
• the orexin-2 receptor antagonist activity of the compounds of formula (I) was determined in accordance with the following experimental method.
• CHO-DG44 cells expressing the human orexin-2 receptor were grown in cell medium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4 mg/ML G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL.
• the cells were seeded at 20,000 cells/100 ⁇ l/well into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 ⁇ g/well of poly-L-lysine from SIGMA. he seeded plates were incubated overnight at 37° C. in 5% CO 2 .
• Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC 50 values (the concentration required to produce 50% maximal response) were estimated using 11 ⁇ half log unit dilutions (Biomek 2000, Beckman) in Tyrode's buffer containing probenecid (10 mM HEPES with 145 mM NaCl, 10 mM glucose, 2.5 mM KCl, 1.5 mM CaCl 2 , 1.2 mM MgCl 2 and 2.5 mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO (100%).
• Antagonist IC 50 values (the concentration of compound needed to inhibit 50% of the agonist response) were determined against 10.0 nM human orexin-A using 11 ⁇ half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid.
• EC50 was the potency of human orexin-A determined in the assay (in nM terms) and IC50 is expressed in molar terms.

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• 2001
  • 2001-11-22 AU AU2002224885A patent/AU2002224885A1/en not_active Abandoned
  • 2001-11-22 WO PCT/EP2001/013687 patent/WO2002044172A1/en active IP Right Grant
  • 2001-11-22 AT AT01994716T patent/ATE286897T1/de not_active IP Right Cessation
  • 2001-11-22 US US10/432,421 patent/US6943160B2/en not_active Expired - Fee Related
  • 2001-11-22 JP JP2002546542A patent/JP4246490B2/ja not_active Expired - Fee Related
  • 2001-11-22 ES ES01994716T patent/ES2234929T3/es not_active Expired - Lifetime
  • 2001-11-22 EP EP01994716A patent/EP1353918B1/de not_active Expired - Lifetime
  • 2001-11-22 DE DE60108420T patent/DE60108420T2/de not_active Expired - Lifetime

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